ABSTRACT: Stroke is the most important cause of adult disability in the United States, leaving more than 60% of its victims struggling to perform daily activities. Post-stroke cognitive impairment (PSCI) is one of the most disabling consequences of stroke occurring in 12%-48% of patients. At a time when stroke mortality is decreasing, the rate of PSCI almost doubled between 1990 and 2000, increasing the urgency for treatment development in this area. A critical barrier to progress in the development of new therapeutic strategies is the lack of understanding of how PSCI develops. The use of almost exclusively male and healthy animals in experimental stroke research has widened this gap in knowledge. Our exciting preliminary data demonstrated a progressive deterioration of cognitive function after experimental stroke, an impairment accentuated by the presence of comorbid diseases such as hypertension and diabetes. We also show the presence of an extended therapeutic window to prevent PSCI. Recent data from the REGARDS study showed that stroke patients also experience a progressive cognitive decline after a single lesion stroke, causing us to rethink how we approach PSCI therapeutically. Accordingly, the goal of this proposal is to define the cellular mechanisms contributing to the chronic build-up of cognitive deficits after stroke. Based on the strong scientific premise of our published and pilot data, our central hypothesis is that progressive cognitive decline is profound when stroke is superimposed on comorbid diseases and involves microglial activation leading to decreased mature brain derived neurotrophic factor (mBDNF) signaling and remodeling in the neurovascular unit. We further hypothesize that Angiotensin type II receptor (AT2) stimulation disrupts this perpetual inflammatory loop and prevents progressive PSCI. 3 integrated translational and mechanistic aims will test these hypotheses; Aim 1: progressive cognitive deficits after stroke, augmented in comorbid conditions, CAN be therapeutically targeted. Aim 2: microglia that are activated to M1-like phenotype after stroke in comorbid disease states, amplify dysregulation of BDNF signaling leading to NVU remodeling and ultimately, progressive PSCI. Aim 3: AT2 stimulation prevents progressive PSCI by promoting M2-like microglial activation and restoration of BDNF signaling in NVU cells. In 10 studies over 5 years, and utilizing rigorous behavioral assessment of aged, hypertensive, and diabetic animals, pharmacologic and genetic manipulation, novel gain and loss-of-function approaches, as well as in vitro assessment, we will advance our understanding of the treatment of PSCI, an understudied yet devastating consequence of ischemic stroke.